The present invention relates to novel endothelin derivatives which are expected to be useful as therapeutic drugs such as agents for improving circulatory functions (for example, therapeutic agents for hypertension or hypotension), therapeutic agents for cardiac or cerebral circulatory diseases (for example, cardiac infarction), and therapeutic agents for renal diseases (for example, acute renal insufficiency); methods for producing the same; and agents for improving circulatory functions mainly comprising the same.
Endothelin (ET) is a vasoconstrictive peptide composed of 21 amino acid residues which was isolated from the culture supernatant of the endothelial cells of porcine aortas and whose structure was determined by M. Yanagisawa et al. in 1988 [M. Yanagisawa et al., Nature 332, 411-415 (1988)]. After that, the research on genes coding for endothelin revealed the presence of peptides similar to endothelin in structure. These peptides are named endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), respectively, and their structures are as follows: ##STR2## (All of the amino acids constituting ET-1, ET-2 and ET-3 take the L-form.) (Inoue et al., Proc. Natl. Acad. Sci. U.S.A. 86, 2863-2867)
The above-mentioned peptides of the endothelin family exist in vivo and have vasopressor activity. For this reason, these peptides are anticipated to be intrinsic factors responsible for the control of circulatory systems, and deduced to be related to hypertension, cardiac or cerebral circulatory diseases (for example, cardiac infarction) and renal diseases (for example, acute renal insufficiency).
If antagonists or agonists of the above-mentioned peptides are obtained, they are considered not only useful for elucidation of the functional mechanism of these peptides, but also they are most likely to be used as effective therapeutic drugs for these diseases. At present, however, no reports are found that an effective antagonist to endothelin has been obtained. Further, it is another subject of the present invention to discover a substance which enhances the activity of endothelin.